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72 Abstracts #55 6.2 HLAANDMALARIA: A CASE-CONTROL STUDY IN AFRICAN CHILDREN. AVS Hill, D Kwiatkowski*, CEM Allsopp, N Anstey , P. Twumasi',, S Abdalla ÷, DR Brewster ÷÷, AJ McMichael, BM Greenwood . Institute of Molecular Medicine, Oxford, UK; MRC Laboratories, Fajara, The Gambia*, St Mary's Hospital, London, U~ and Royal Victoria Hospital, Banjul, The Gambia ÷÷. We have performed a large hospital-based case-control study of the influence of HLA alleles on susceptibility to P.falciparum malaria in the West African population of the Gambia. 1570 children were classified into four groups: i) severe cerebral malaria; ii) severe malarial anaemia; iii) mild malaria; iv) controls without malaria. The latter were matched to the malaria cases for age (mean 3.5 years) and area of residence around Banjul. Mortality in the children with severe malaria was 15%. The carrier rate of Hemoglobin S was found to be 10% in the non- malaria controls and 1% in the severe malaria groups. HLA class II typing of these children using a combination of RFLP and PCR-oligonucleotide analysis revealed a significant decrease in the frequency of the common Gambian HLA class II haplotype DRwI3-DRw52c-DQwl in the severe malarial anaemia group (allele frequency 9% v. 16%, RR=0.56, p=0.0015) with a smaller decrease in the cerebral malaria group. Serological analysis of HLA class I alleles to date suggests a similar decrease in frequency of HLA- Bw53 in both severe malaria groups. These data suggest that some common African HLA alleles have been subject to natural selection by P. falciparum malaria. #56 6.2 LACK OF LINKAGE DISEQUILIB}{IUM BETWEEN HLA DQ BETA RESTRICTION FRAGMENT LENGTH POLYMORPHISMS AND AUTOIMMUNE THYROID DISEASE. G. O'Connor, DS Neufeld, DA Greenberg, L Concepcion, SH Roman and TF Davies. Departments of Medicine and Psychiatry, Mr. Sinai School of Medicine NY. Autoimmune thyroid diseases (AITD) are often familial and HLA disease population associations have been weak; also, in recent reports they appear not to be apparent within affected families. The purpose of this study was to test for linkage disequilibrium between the HLA DQ- beta locus and AITD in multiplex and multigenerational families. 38 subjects in 7 families (3 multiplex and 4 multigenerational) were studl.zd. 6 subjects had Graves' disease and Ii had Hashimoto's thyroiditis. DNA was isolated from whole blood, digested with the restriction endonuclease BamHl, transferred to nitrocellulose membranes and probed with a radioactively labelled full length DQ-beta cDNA probe. Segregation of polymorphic fragments enabled genotyping of each individual from a pool of 4 parental types. Using the program LIPED, lod scores were computed for dominant and recessive models of inheritance, for recombination fractions of 0.01 to 0.5 for each sex, and for penetrances from 0.i to 1.0. The results showed that maximum LOD scores were negative for all of the inheritance models tested. Since linkage requires lod scores of 3 or more, this is strong evidence against linkage disequilibrium between the HLA DQ locus and AITD.

HLA and Malaria: A case-control study in African children

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Page 1: HLA and Malaria: A case-control study in African children

72 Abstracts

#55 6.2

HLAANDMALARIA: A CASE-CONTROL STUDY IN AFRICAN CHILDREN. AVS Hill, D Kwiatkowski*, CEM Allsopp, N Anstey , P. Twumasi',, S Abdalla ÷, DR Brewster ÷÷, AJ McMichael, BM Greenwood . Institute of Molecular Medicine, Oxford, UK; MRC Laboratories, Fajara, The Gambia*, St Mary's Hospital, London, U~ and Royal Victoria Hospital, Banjul, The Gambia ÷÷ .

We have performed a large hospital-based case-control study of the influence of HLA alleles on susceptibility to P.falciparum malaria in the West African population of the Gambia. 1570 children were classified into four groups: i) severe cerebral malaria; ii) severe malarial anaemia; iii) mild malaria; iv) controls without malaria. The latter were matched to the malaria cases for age (mean 3.5 years) and area of residence around Banjul. Mortality in the children with severe malaria was 15%. The carrier rate of Hemoglobin S was found to be 10% in the non- malaria controls and 1% in the severe malaria groups. HLA class II typing of these children using a combination of RFLP and PCR-oligonucleotide analysis revealed a significant decrease in the frequency of the common Gambian HLA class II haplotype DRwI3-DRw52c-DQwl in the severe malarial anaemia group (allele frequency 9% v. 16%, RR=0.56, p=0.0015) with a smaller decrease in the cerebral malaria group. Serological analysis of HLA class I alleles to date suggests a similar decrease in frequency of HLA- Bw53 in both severe malaria groups. These data suggest that some common African HLA alleles have been subject to natural selection by P. falciparum malaria.

#56 6.2

LACK OF LINKAGE DISEQUILIB}{IUM BETWEEN HLA DQ BETA

RESTRICTION FRAGMENT LENGTH POLYMORPHISMS AND AUTOIMMUNE

THYROID DISEASE. G. O'Connor, DS Neufeld, DA Greenberg,

L Concepcion, SH Roman and TF Davies. Departments of

Medicine and Psychiatry, Mr. Sinai School of Medicine NY.

Autoimmune thyroid diseases (AITD) are often familial

and HLA disease population associations have been weak;

also, in recent reports they appear not to be apparent

within affected families. The purpose of this study was

to test for linkage disequilibrium between the HLA DQ-

beta locus and AITD in multiplex and multigenerational

families. 38 subjects in 7 families (3 multiplex and 4

multigenerational) were studl.zd. 6 subjects had Graves'

disease and Ii had Hashimoto's thyroiditis. DNA was

isolated from whole blood, digested with the restriction

endonuclease BamHl, transferred to nitrocellulose

membranes and probed with a radioactively labelled full

length DQ-beta cDNA probe. Segregation of polymorphic

fragments enabled genotyping of each individual from a

pool of 4 parental types. Using the program LIPED, lod

scores were computed for dominant and recessive models

of inheritance, for recombination fractions of 0.01 to

0.5 for each sex, and for penetrances from 0.i to 1.0.

The results showed that maximum LOD scores were negative

for all of the inheritance models tested. Since linkage

requires lod scores of 3 or more, this is strong evidence

against linkage disequilibrium between the HLA DQ locus

and AITD.